Forensic Science International 152 (2005) 175–184

www.elsevier.com/locate/forsciint

Determination of synthesis method of ecstasy based

on the basic impurities
M. Śwista,*, J. Wilamowskib, A. Parczewskia,c
a
Department of Analytical Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
b
Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
c
Institute of Forensic Research, Westerplatte 9, 31-033 Krakow, Poland

Received 6 April 2004; received in revised form 30 July 2004; accepted 2 August 2004
Available online 25 September 2004

Abstract

MDMA was prepared by five different synthesis routes, i.e. by dissolving metal reduction (Al/Hg), cyanoborohydride
reduction (NaBH3CN), borohydride reduction in low temperature (NaBH4), Leuckart reaction and safrole bromination. MDP-2-
P was prepared by two different synthesis methods, i.e. by isosafrole oxidation and MDP-2-nitropropene reduction. Each of the
synthesis routes was repeated three times in order to establish variation in qualitative composition of route specific impurities
between different batches. The analysis of impurities in MDP-2-nitropropene, MDP-2-P, bromosafrole and MDMA was
performed with GC-MS. GC/MS was used also in the analysis of impurities in starting materials: safrole, isosafrole and
piperonal. As a result of our study the way of determination of MDMA synthesis route determination based on qualitative
composition of impurities is proposed.
# 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: MDMA; Reductive amination; Leuckart method; Safrole bromination; Route specific impurities

1. Introduction In illegal production of ecstasy (MDMA) the most

The increasing number of ‘ecstasy’ tablets seized by
European law-enforcement agencies dealing with drugs,
such as the police, customs, border guards, special drug
agencies, etc., shows that illegal production of ‘ecstasy’, a
synthetic derivative of amphetamine, has been risen during
last decades. Western Europe is now recognized as the
primary source of the world’s ‘ecstasy’. But illegal produc-
tion of ‘ecstasy’ is not only a problem of the European.
Clandestine laboratories are seized all over the world, in
Africa, Asia, North and South America.
* Corresponding author. Tel.: +48 12 633 6377x2014;
fax: +48 12 634 0515.
E-mail address: brozek@chemia.uj.edu.pl (M. Świst).
popular synthesis method is reductive amination of MDP-
2-P (PMK) [1–5]. Within this method diversity of approa-
ches exists because different reducing agents can be used.
The most often encountered are borohydride (NaBH4)
reduction in low temperature, dissolving metal reduction
(Al/Hg) and cyanoborohydride reduction (NaBH3CN)
(Fig. 1). Apart from these methods Leuckart reaction
(Fig. 2) and safrole bromination (Fig. 3) are also used. It
is worth while to mention that in illegal production of
amphetamine Leuckart reaction is used predominantly [6].
Each sample of synthetic drug has its own, characteristic
composition of impurities dependent on the way of its
production and preparation for distribution. This enables
comparative analysis of the drugs seizures. Moreover, there
is also possibility of identification of synthesis method on the
base of by-products and intermediates, as well as precursors,

0379-0738/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.forsciint.2004.08.003
176 M. Świst et al. / Forensic Science International 152 (2005) 175–184

ether, toluene, isopropanol, hydrogen peroxide (33%),

Fig. 1. The scheme of reductive amination methods.
i.e. starting materials, which are at the source of many by-
products.
Some studies devoted to route specific impurities of
MDMA and MDA have already been done [7–13], but in
most cases impurities were identified in reaction mixtures.
The precipitate of MDMA
HCl was very rarely investigated.
sulfuric acid (95%) (all POCh, Poland, analytical grade),
piperonal (99%, Aldrich), isosafrole (97%, Aldrich), safrole
(97%, Aldrich), nitroethane (96%, Aldrich), cyclohexyla-
mine (99%, Aldrich), ethyl formate (97%, Aldrich), hydro-
bromic acid (62%, Aldrich), methylamine solution (33% in
abs. ethyl alcohol) methylamine aqueous solution (40%,
Aldrich), diethyl ether (anhydrous, >99%, A.C.S. Reagent),
methanol (HPLC grade, Merck), NaBH4 (Aldrich, for synth-
esis), NaBH3(CN) (Aldrich, for synthesis).
In impurity profiling experiments the following reagents
were used: carbonate buffer pH 10 (10.7 ml 0.1 M NaOH,
50 ml 0.05 M NaHCO3, 39.3 ml H2O), n-heptane (Aldrich,
HPLC grade), diphenylamine (Supelco, used as internal
standard).

2. Materials and methods 2.2. Syntheses

2.1. Chemicals and reagents
In synthesis the following reagents were used: formic
acid (98%), hydrochloric acid (36–38%), methylene chlor-
ide, sodium hydroxide, acetic acid (99.5%), acetone, diethyl
The following synthesis methods of MDP-2-P and
MDMA have been chosen by the authors according to the
preferences of the clandestine laboratories. The physical and
spectral (IR, NMR) properties of all synthesized compounds
were identical with the data reported formerly [14].

Fig. 2. The scheme of Leuckat method.

Fig. 3. The scheme of MDMA synthesis by safrole bromination followed by methylamine substitution.

Fig. 5. The scheme of MDP-2-P synthesis by MDP-2-nitropropene

Fig. 4. The scheme of MDP-2-P synthesis by isosafrole oxidation. reduction.
 M. Świst et al. / Forensic Science International 152 (2005) 175–184 177

Table 1
Variation in qualitative composition of route specific impurities between different batches
Compound number Compound structure The number of synthesis repetition
L B R
1 2 3 1 2 3 1 2 3
1 0 0 0 0 0 0 0 0 0

2 (++) (++) (++) 0 0 0 (++) (++) (++)

3 (+) (+) (+) 0 0 0 (+) (+) (+)

4 (++) (++) (++) 0 0 0 (+++) (+++) (+++)

5 (+++) (+++) (+++) 0 0 0 (+) (+) (+)

6 (++) (++) (++) 0 (+) 0 0 0 0

7 (+) (+) (+) 0 0 0 0 0 0

8 (+++) (+++) (+++) (+++) (+++) (+++) 0 0 0

9 (+++) (+++) (+++) (+) (+) (+) 0 0 0

10 0 0 0 (+++) (+++) (+++) 0 0 0

11 0 0 0 (+++) (+++) (+++) 0 0 0

12 (++) (++) (++) (++) (++) (++) (+) (+) (+)

13 (+) (+) (+) 0 0 0 0 0 0

L: Leuckart method, B: safrole bromination, R: borohydride reduction in low temperature; 0: absent in impurity profile; (+): percentage of total
area <0.05%; (++): percentage of total area >0.05% and <1%; (+++): percentage of total area >1%.
178 M. Świst et al. / Forensic Science International 152 (2005) 175–184
MDP-2-P was synthesized by two different routes, i.e. by
oxidizing isosafrole in an acid medium (Fig. 4) and by
reduction of 1-(3,4-methylenedioxyphenyl)-2-nitropropene,
which was previously prepared by condensation of piperonal
and nitroethane (Fig. 5). The syntheses were performed
according to the procedures described by Al. Shulgin and
A. Shulgin [15].
2.2.1. MDMA prepared by reductive amination
This is the most popular synthesis route of MDMA in
illegal production. However, within this method diversity of
approaches exists because of possibility of application var-
ious reducing agents. We have synthesized MDMA accord-
ing to the following approaches (Fig. 1):
 Dissolving metal reduction using aluminium–mercury
amalgam. This synthesis was performed according to
the procedure described by Al. Shulgin and A. Shulgin
[15].
 Borohydride (NaBH4) reduction. This synthesis was per-
formed according to the following procedure: aqueous
solution (40%) of methylamine (2 ml) was added to a cold
mixture of MDP-2-P (1.51 g) in MeOH (5 ml). The
mixture was cooled to 20 8C and then NaBH4
(30 mg) was slowly added. After dissolving of reductive
agent, reaction mixture was left at 20 8C for 2 h. The
addition of NaBH4 was repeated three times, in portions of
30, 30 and 40 mg, and reaction mixture was left at 20 8C
for 24 h. Methanol was evaporated, 10% HCl (10 ml) was
added to a residue, and the solution was washed with
CH2Cl2 (3 ml  8 ml). The organic solution was extracted
Fig. 6. Some differences and similarities in impurity composition in MDMA samples prepared by different synthesis methods.
with 10% HCl, combined aqueous layers were alkalized
with 25% NaOH (10 ml) and extracted with CH2Cl2
(3  10 ml). Combined extracts were dried over MgSO4,
evaporated, a residue was dissolved in Et2O (18 ml) and
dry HCl was passed through the solution. Precipitate of
MDMA
HCl was filtered off and dried.
 Cyanoborohydride (NaBH3CN) reduction. This synthesis
was performed according to the modified MDA synthesis
procedure described by Al. Shulgin and A. Shulgin [15].
2.2.2. MDMA prepared by Leuckart method
This synthesis was performed according to the modified
MDA synthesis procedure described by Elks and Hey [16]
(Fig. 2).
2.2.3. MDMA prepared by safrole bromination
This synthesis was performed according to the procedure
described by Biniecki and Krajewski [17] (Fig. 3).
2.3. Sample preparation
Safrole (0.015 g), piperonal (0.015 g), isosafrole (0.015 g),
MDP-2-nitropropene (0.015 g), MDP-2-P (0.015 g) and bro-
mosafrole (0.015 g) were dissolved in 200 ml of Et2O and
analyzed using GC/MS.
Extraction of impurities was performed as follows: a
portion of 200 mg of MDMA
HCl was dissolved in 2 ml of
carbonate buffer (pH 10), the solution was then vigorous
shaken (25 min) following by addition of 200 ml of n-
heptane containing diphenylamine as an internal standard
 M. Świst et al. / Forensic Science International 152 (2005) 175–184 179

Fig. 8. One of the side-reaction occurring during safrole bromina-

tion method.
Fig. 7. One of the side-reaction occurring during reductive amina-
tion and Leuckart method.

(35 mg/l), and then again shaken (25 min). The extracts were 1 min, then ramped at 10 8C/min up to 150 8C, maintained
subjected to GC/MS analysis and impurity profiles were 5.5 min, and again increased to 280 8C at 10 8C/min ramp,
obtained. and maintained for the final 10 min. Mass spectrometer was
operated in positive electron ionization mode (EI). A full-
2.4. Apparatus scan mass spectra 40–500 amu were obtained.

GC/MS analysis was carried out on Hewlett-Packard

6890 series gas chromatograph coupled to 5984B mass
spectrometer. HP5-MS fused silica capillary column
(30 m  0.25 mm  0.25 mm) was applied and helium
6.0 was used as a carrier gas (1.0 ml/min). The injection
(2 ml) was made splitless by the autosampler. The following
temperature program was applied: 50 8C maintained for
3. Results and discussion
Synthesis according to each given method was repeated
three times according to the same procedure in order to
establish variation in qualitative composition of route spe-
cific impurities between different batches. The results are

Fig. 9. The mass spectrum of N-methyl-N-[1-methyl-2-(3,4-methylenedioxyphenyl)-ethyl)]-3-(3,4-methylenedioxyphenyl)-propaneamine.

180 M. Świst et al. / Forensic Science International 152 (2005) 175–184

Fig. 10. The proposed fragmentation of N-methyl-N-[1-methyl-2-(3,4-methylenedioxyphenyl)-ethyl)]-3-(3,4-methylenedioxyphenyl)-propa-

neamine.

presented in Table 1. Generally, the qualitative composition oxidation. The other compounds are characteristic for only
of route specific impurities does not change between dif- one method, although compound 6 is sometimes found in
ferent batches of the same synthetic route. But we found that MDMA samples prepared by safrole bromination. Com-
some of these impurities may emerge unexpectedly in other pound 7 is produced in reaction of camphor (which has its
methods. Therefore, instead of individual compounds, source in isosafrole) with methylamine. In the case of
the groups of markers should be always considered for synthesis marker of reductive amination (compound 1) we
determination of synthetic route. found that it might not be present in impurity profiles if the
Diagram in Fig. 6 shows how to identify synthesis synthesis is performed with good yield, as it was in case of
method of ecstasy on the base of the basic impurities. borohydride reduction in low temperature (Table 1) and
As can be seen in this diagram each synthesis method has dissolving metal reduction. Only in cyanoborohydride
its own characteristic group of impurities. Identification of reduction this compound was identified in impurity pro-
one of this group in impurity profiles of MDMA is equiva- files. The markers of safrole bromination, compounds 10
lent with the identification of synthesis method. It appears
that majority of impurities included in this diagram occur
in MDMA
HCl in higher concentration as compare to
other impurities. Some of them are common for not more
than two methods although the mechanisms of their for-
mation are sometimes different. This concerns compounds
8 and 9 which emerge in Leuckart reaction as well as safrol
bromination. In the case of common impurities of Leuckart
and reductive amination methods the mechanism of their
formation is the same, i.e. compounds 2 and 3 emerge
during reaction of methylamine impurities and piperonal,
as was reported formerly [2] and compound 5 is a product
of reaction of N-methyl-3,4-methylenedioxybenzylamine
with MDP-2-P (Fig. 7). The compound 4 is a product of
reaction of impurity of MDP-2-P, 1-methoxy-1-(3,4-
methylenodioxyphenyl)-2-propanone, with methylamine, Fig. 11. The formation of N-methyl-2-methyl-1-(3,4-methylene-
so it is not only the marker of Leuckart and reductive dioxyphenyl)-ethaneamine (compound 12) in safrole bromination
amination but also synthesis of MDP-2-P by isosafrole method and Leuckart method.
 M. Świst et al. / Forensic Science International 152 (2005) 175–184 181

Fig. 12. The mass spectrum of 1-(3,4-methylenedioksyphenyl)-1-propanone.

and 11 were found only in samples prepared by this
method (Fig. 8). The mass spectrum of compound 11 is
presented in Fig. 9 and proposed fragmentation pattern of
this compound is present in Fig. 10.
Moreover, in identification of synthesis method the fol-
lowing information could be used. During MDMA synthesis
by Leuckart method as well as safrole bromination the
compound 12 (Table 1) is produced. In case of Leuckart
method compound 12 arise in reaction of MDP-2-P impurity,
1-(3,4-methylenedioxyphenyl)-1-propanone, and methyla-
mine (Fig. 11). The mass spectra of both subtract and
product of this reaction are presented in Figs. 12 and 13.

Fig. 13. The mass spectrum of N-methyl-2-methyl-1-(3,4-methylenedioxyphenyl)-ethaneamine (compound 12).

182 M. Świst et al. / Forensic Science International 152 (2005) 175–184

Fig. 14. The mass spectrum of N-methyl-1-(3,4-methylenedioxyphenyl)-ethaneamine (compound 13).

But in case of safrole bromination compound 12 is produced
in reaction of 1-bromo-1-(3,4-methylenedioxyphenyl)pro-
pane. In reductive amination compound 12 is present in
impurity profiles of ecstasy but at a very low concentration in
comparison to other impurities and this fact facilitates
the discrimination of Leuckart reaction from reductive
amination.
In discrimination the Leuckart reaction from safrole
bromination could be used fact, that compound 13 (Table 1,
Fig. 14) is not produced during safrole bromination.

Fig. 15. The mass spectrum of 2-(dimethylamino)-2-methyl-3-(3,4-methylenedioxyphenyl)-propanenitrile.

 M. Świst et al. / Forensic Science International 152 (2005) 175–184 183

Fig. 16. The mechanism of 2-(dimethylamino)-2-methyl-3-(3,4-methylenedioxyphenyl)-propanenitrile formation in cyanoborohydride

reduction.

Fig. 17. The mass spectrum of N-methyl-2-methoxy-1-methyl-2-(3,4-methylenedioxyphenyl)-ethaneimine.

Fig. 18. The ways of formation of PMMA from impurity in safrole, 1-methoxy-4-(2-propenyl)-benzene.
184 M. Świst et al. / Forensic Science International 152 (2005) 175–184
We found that different variants of reductive amination
might be also discriminated. For example we identified
marker of cyanoborohydride reduction (NaBH3CN), 2-
(dimethylamino)-2-methyl-3-(3,4-methylenedioxyphenyl)-
propanenitrile. Mass spectrum of this compound is pre-
sented in Fig. 15 and the mechanism of its formation is
presented in Fig. 16. In impurity profiles of MDMA samples
prepared by this method we also identified an imine corre-
sponding to compound 4, which mass spectrum is presented
in Fig. 17. All these compounds were identified only in this
method.
GC/MS analysis of commercially available safrole and
isosafrole proved that 1-methoxy-4-(2-propenyl)-benzene is
only present in safrole (Fig. 18). Because of the fact that even
its isomer, 1-methoxy-4-(1-propenyl)-benzene, is not pre-
sent in isosafrole, there is a possibility to find out whether
synthesis of MDMA was started from safrole or isosafrole on
the basis of presence or absence of PMMA (p-methoxy-
methamphetamine) in impurity profiles. If commercially
available safrole was used as a starting material to produce
isosafrole (via isomerization reaction) or bromosafrole, then
it should results in presence of PMMA in impurity profiles of
MDMA The absence of PMMA in impurity profiles of
MDMA indicates that probably commercially available
isosafrole was used as a starting material.
4. Conclusions
The route specific impurities were identified in impurity
profiles of MDMA prepared by five different synthesis
methods. Some of them have not been reported formerly.
The way of synthesis route determination based on quali-
tative composition of impurities is proposed. Additionally,
variation in qualitative composition of route specific impu-
rities between different batches is evaluated.
Acknowledgments
This study was supported by a grant OT 00C 01024 from
the Committee for Scientific Research, Poland.
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